Texaphyrin compounds are described in U.S. Pat. Nos. 4,935,498, 5,162,509, 5,252,720, 5,272,142 and 5,256,399, each of which is incorporated by reference herein. Texaphyrin refers to an "expanded porphyrin" pentadentate macrocyclic ligand. The compound is capable of existing in both its free-base form and of supporting the formation of a 1:1 complex with a variety of metal cations, such as Cd.sup.2+, Hg.sup.2+, In.sup.3+, Y.sup.3+, Nd.sup.3+, Eu.sup.3+, Sm.sup.3+, La.sup.3+, Lu.sup.3+, Gd.sup.3+, and other cations of the lanthanide series that are too large to be accommodated in a stable fashion within the 20% smaller tetradentate binding core of the well-studied porphyrins.
Large, or "expanded" porphyrin-like systems are of interest for several reasons: They could serve as aromatic analogues of the better studied porphyrins or serve as biomimetic models for these or other naturally occurring pyrrole-containing systems. In addition, large pyrrole containing systems offer possibilities as novel metal binding macrocycles. For instance, suitably designed systems could act as versatile ligands capable of binding larger metal cations and/or stabilizing higher coordination geometries than those routinely accommodated within the normally tetradentate ca.2.0.ANG. radius porphyrin core. The resulting complexes could have important application in the area of heavy metal chelation therapy, serve as contrast agents for magnetic resonance imaging (MRI) applications, act as vehicles for radioimmunological labeling work, or serve as new systems for extending the range and scope of coordination chemistry.
A number of pentadentate polypyrrolic aromatic systems, including the "sapphyrins", "oxosapphyrins", "smaragdyrins", "platyrins" and "pentaphyrin" have been prepared and studied as their metal-free forms. A "superphthalocyanine" system is not capable of existence in either its free-base or other metal-containing forms. Thus, prior to the present inventors' studies, no versatile, structurally characterized, pentadentate aromatic ligands were available.
The water-soluble porphyrin derivatives, such as tetrakis(4-sulfonatophenyl)porphyrin (TPPS) cannot accommodate completely the large gadolinium(III) cation within the relatively small porphyrin binding core (r.congruent.2.0.ANG.), and, as a consequence, gadolinium porphyrin complexes are invariably hydrolytically unstable.
Photodynamic therapy (PDT) uses a photosensitizing dye, which localizes at, or near, a treatment site, and when irradiated in the presence of oxygen serves to produce cytotoxic materials, such as singlet oxygen (O.sub.2 (.sup.1 .DELTA..sub.g)), from benign precursors (e.g. (O.sub.2 (.sup.3 .SIGMA. .sub.g -)). While porphyrin derivatives have high triplet yields and long triplet lifetimes (and consequently transfer excitation energy efficiently to triplet oxygen), their absorption in the Q-band region parallels that of heme-containing tissues.
Hematoporphyrin derivative and Photofrin II.RTM. (oligomeric hematoporphyrin derivative) act as efficient photosensitizers for the photo-deactivation of cell-free HIV-1, herpes simplex (HSV), hepatitis and other enveloped viruses in far lower dosages than are required for tumor treatment. The success of this procedure derives from the fact that these dyes localize selectively at or near the morphologically characteristic, and physiologically essential, viral membrane ("envelope") and catalyze the formation of singlet oxygen upon photoirradiation. The singlet oxygen destroys the essential membrane envelope. This kills the virus and eliminates infectivity. Photodynamic blood purification procedures, therefore, rely on the use of photosensitizers which localize selectively at viral membranes.
In contrast to the literature of the porphyrins, and related tetrapyrrolic systems (e.g. phthalocyanines, chlorins, etc.), there are only a few reports of larger pyrrole-containing systems, and only a few of these meet the criterion of aromaticity deemed essential for long-wavelength absorption and singlet oxygen photosensitization. In addition to the present inventors' studies of texaphyrin, and "sapphyrin", first produced by Bauer et al. (1983) and Broadhurst et al. (1972) there appear to be only three large porphyrin-like systems which might have utility as photosensitizers. These are the "platyrins" of LeGoff et al. (1987), the stretched porphycenes of Vogel et al. (1990) and the vinylogous porphyrins of Gosmann et al. (1986). The porphycenes, (Vogel et al. 1986, Vogel et al. 1987), a novel class of "contracted porphyrins" also show promise as potential photosensitizers, (Aramendia et al. 1986).
The lowest energy Q-type band of the structurally characterized bispyridine cadmium(II) adduct of texaphyrin at 767 nm (.epsilon.=51,900) in CHCl.sub.3 is 10-fold more intense and red shifted by almost 200 nm as compared to that of a typical reference cadmium(II) porphyrin. Zinc(II) and cadmium(II) complexes of texaphyrin are effective photosensitizers for singlet oxygen, giving quantum yields for .sup.1 O.sub.2 formation of between 60 and 70% when irradiated at 354 nm in air-saturated methanol, (Harriman et al. 1989). Related congeneric texaphyrin systems bearing substituents on the tripyrrole and/or phenyl portions and incorporating La(III) and/or Lu(III) metal centers have been found to produce .sup.1 O.sub.2 in quantum yields exceeding 70% when irradiated under similar conditions. Thus, it is this remarkable combination of light absorbing and .sup.1 O.sub.2 photo-sensitizing properties which makes these systems ideal candidates for use in photodynamic therapy and blood purification protocols.
The desirable properties of texaphyrins are:
1) appreciable solubility, particularly in aqueous media;
2) biolocalization in desired target tissue;
3) low intrinsic toxicity;
4) the ability to attach to solid matrices;
5) the ability to be attached to biomolecules;
6) efficient chelation of divalent and trivalent metal cations;
7) absorption of light in the physiologically important region of 690-880 nm;
8) high chemical stability;
9) ability to stabilize diamagnetic complexes that form long-lived triplet states in high yield and that act as efficient photosensitizers for the formation of singlet oxygen;
10) ability to chelate Gd(III) for magnetic resonance imaging;
11) a redox potential lower than that of oxygen for use as a radiosensitizer.
One of the disadvantages of the texaphyrin metal complexes of the parent patent applications is their short half-life. The Y.sup.3+ and In.sup.3+ complexes of texaphyrin have half-lives for decomplexation and/or ligand decomposition of about 3 weeks in 1:1 methanol-water mixtures. While such stability is adequate for some in vitro or in vivo applications, a greater degree of stability in aqueous solution is desirable. For example, a desired solution-phase shelf life of 2-3 years would facilitate the formulation of texaphyrin metal complexes as pharmaceutical products. The new molecules of the present invention address the problems of demetallation of the texaphyrin metal complex and the susceptibility of the imine bonds of the macrocycle to hydrolysis. The solution to these problems is expected to provide a texaphyrin which has a more desirable shelf life.